Compositions and methods for treating, reducing, ameliorating, or preventing infections

ABSTRACT

Compositions for treating, reducing, ameliorating, or preventing infections comprise a fluoroquinolone having Formulae I-VIII and an additional anti-infective agent. Methods for treating, reducing, ameliorating, or preventing such infection use such compositions. Such compositions and methods can be effective against mixed types of pathogens including certain antibiotic-resistant microbial pathogens found in such infections.

CROSS REFERENCE

This application is a divisional of patent application Ser. No.12/115,914 filed May 6, 2008 and claims the benefit of ProvisionalPatent Application No. 60/938,765 filed May 18, 2007 which isincorporated by reference herein.

BACKGROUND OF THE INVENTION

The present invention relates to compositions and methods for treating,reducing, ameliorating, or preventing infections. In particular, thepresent invention relates to such compositions comprising a quinolonecarboxylic acid or a derivative thereof, and an additionalanti-infective medicament; and to methods of using such compositions.More particularly, the present invention relates to such compositionscomprising a fluoroquinolone carboxylic acid or a derivative thereof,and an additional anti-infective medicament; and to methods of usingsuch compositions.

Pathogens continue to pose a serious threat to public health asindicated by a worldwide resurgence of diseases caused by bacteria,fungi, and/or viruses. Infections by pathogenic microorganisms affect alarge number of patients every year. Common infections include those ofthe ear, respiratory system, and eye. An experienced medicalpractitioner often can determine the etiology of an infection and,therefore, prescribe an effective treatment. However, infections areoften caused by mixed types of microorganisms that may not beimmediately obvious on presentation. Consequently, an initial treatmentregimen may not be immediately effective and must be replaced withanother. In cases where the patients are especially vulnerable, such asthose with a compromised immune system, a delayed onset of a beneficialeffect of the treatment may lead to increased risk of more seriouscomplications.

Otitis media, an infection of the middle ear, is a major worldwideinfection in children. By the age of 2 years, seventy percent ofchildren have experienced at least one episode of acute otitis media(“AOM”). T. Heikkinen et al., Clin. Microbiol. Rev., Vol. 16, No. 2, 230(2003). Otitis media can also occur in adults. AOM is generallyconsidered a bacterial infection that is treated with antibiotics. Thethree most common bacteria isolated from the middle ear fluid (“MEF”)are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxellacatarrhalis. See; e.g., J. T. Kirchener, American Family Physician, Apr.15, 1999. However, since the 1980s, viruses have also been detected inthe MEF of children with AOM in approximately twenty percent of thecases. T. Heikkinen et al., supra. The common respiratory viruses suchas human rhinovirus, respiratory syncytial virus, influenza viruses, andcoronavirus, have been found in children MEF. In addition, in a recentstudy, fungal DNA was detected in MEF of some patients with recurrentAOM and serous otitis media.

In cases of otitis externa, an infection of the external ear canal,mixed bacteria and fungi have often been found. Pseudomonas aeruginosaand Staphylococcus aureus are the most common bacteria species, andAspergillus and Candida fungus species account for over ninety percentof the cases in which fungi are present. However, fungus is occasionallythe primary pathogen in otitis externa, especially in the presence ofmoisture and heat. R. Sander, American Family Physician, Vol. 63, No. 5,927 (2001).

Infections of the upper respiratory system are also common. The commoncold is mostly of viral etiology. However, bacteria and fungi have alsooften caused other infections of the upper respiratory system. Bacteriaare the most common infectious agents in sinusitis. Streptococcuspneumoniae, Haemophilus influenzae, and Moraxella catarrhalis have beenfound in most of cases of sinusitis. Other possible bacterial culpritsinclude other streptococcal strains and Staphylococcus aureus. Whilefungi are an uncommon cause of sinusitis, the incidence of suchinfections is increasing. The most common fungi involved in sinusitisare Asperillus species; in particular, Asperillus fumigatus. Other fungithat can cause sinusitis include Curvularia (in particular, Curvularialunata), Bipolaris, Exserohilum, and Mucomycosis. See, Sinusitis, athttp://adam.about.com (visited on Feb. 20, 2007). While fungal sinusitisis mostly non-invasive and does not lead to serious complications, rarecases of invasive fungal sinusitis caused by the fungus Scopulariopsisacremonium have been reported. Invasive fungal sinusitis is potentiallyfatal for immunocompromised patients. M. D. Ellison et al., Arch.Otolaryngol. Head Neck Surg., Vol. 124, 1014 (1998). It can lead totissue invasion and destruction of adjacent structures (e.g., orbit,central nervous system). Therefore, early detection and treatment arevital for these patients.

Keratitis and conjunctivitis, two common ocular infections, are causedmostly by bacteria, fungi, and/or viruses. Numerous cocci(Staphylococcus, Streptococcus, and Neisseria species) and bacilli(Corynebacterium, Propionobacterium, Clostridium, Pseudomonas,Klebsiella, Hemophilus, Moraxella, Proteus, Serratia, Escherichia, andEnterobacter species) have been isolated from cases of ocularinfections. Among the fungi causing ocular infections are Aspergillus,Fusarium, and Candida species. Herpes simplex virus (“HSV”), Varicellazoster virus, Andenovirus, and Molluscum contagiosum have been found incases of viral ocular infections. See; e.g., G. M. Bohigian and ShailajaValluri, in Handbook of Ocular Infections, Inflammation, and ExternalDiseases, Chapter 2. Moreover, several studies have identified mixedmicroorganism types in ocular infections, such as mixtures of bacteriaand HSV, bacteria and Andenovirus, or bacteria and fungi. See; e.g., M.J. Bharathi et al., Br. J. Ophthalmol., 90, 1271 (2006); S. K. Basak,Indian J. Ophthalmol., Vol. 53, No. 1, 17 (2005).

An additional challenge in the treatment of infections is the emergenceof bacterial resistance to antibiotics. Such resistance may beattributed to prior widespread, and largely effective, therapeutic andprophylactic use of antibiotics, which, unfortunately, over time hasalso selected for resistant strains of various bacterial pathogens. Ofparticular concern to the public health have been the emergence andproliferation of bacterial strains that are resistant to multipleantibiotics in the current arsenal of antimicrobial agents. Therefore, acondition may not respond to an initially prescribed therapy, and, insuch a case, another medicament must be given, resulting in delayedcontrol of the pathogen.

Therefore, there is a continued need to develop improved pharmaceuticalcompositions that can begin to provide benefits to patients in combatinginfections that do not have clear etiology, soon after beingadministered to the patients. It is also very desirable to providepharmaceutical compositions that minimize the risk of complications ofthe primary infection due to the delayed onset of effectiveness of thetreatment.

SUMMARY OF THE INVENTION

In general, the present invention provides pharmaceutical compositionsand methods using such compositions for the treatment, reduction,amelioration, or prevention of infections.

In one aspect, the present invention provides pharmaceuticalcompositions and methods using such compositions for the treatment,reduction, amelioration, or prevention of infections of an eye, an ear,a portion of a respiratory system, or a combination thereof.

In another aspect, an etiology of such infections is not readilyascertainable upon presentation.

In still another aspect, such infections are caused by mixed types ofmicroorganisms.

In still another aspect, such compositions comprise: (a) at least onemember of a family of fluoroquinolones that have Formula I or saltsthereof; and (b) an additional anti-infective medicament; wherein

wherein R¹ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted lower alkyl groups,cycloalkyl groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, and groups that can be hydrolyzed in living bodies;R² is selected from the group consisting of hydrogen, unsubstitutedamino group, and amino groups substituted with one or two lower alkylgroups; R³ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted lower alkyl groups,cycloalkyl groups, unsubstituted lower alkoxy groups, substituted loweralkoxy groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄ arylgroups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, unsubstituted C₅-C₂₄ aryloxy groups, substitutedC₅-C₂₄ aryloxy groups, unsubstituted C₅-C₂₄ heteroaryloxy groups,substituted C₅-C₂₄ heteroaryloxy groups, and groups that can behydrolyzed in living bodies; X is selected from the group consisting ofhalogen atoms; Y is selected from the group consisting of CH₂, O, S, SO,SO₂, and NR⁴, wherein R⁴ is selected from the group consisting ofhydrogen, unsubstituted lower alkyl groups, substituted lower alkylgroups, and cycloalkyl groups; and Z is selected from the groupconsisting of oxygen and two hydrogen atoms; and wherein thecompositions are capable of inhibiting a growth or survival of mixedtypes of microorganisms causing said infections.

In still another aspect, said additional anti-infective medicamentcomprises a quinolone other than those represented by Formula I.

In still another aspect, said additional anti-infective medicamentcomprises a quinolone other than those represented by Formula I, andanother agent selected from the group consisting of antiviral agents,antifungal agents, antiprotozoal agents, and combinations thereof.

In yet another aspect, said additional anti-infective medicament isselected from the group consisting of antifungal agents, antiviralagents, and combinations thereof.

In a further aspect, a composition of the present invention comprises asingle enantiomer of a compound having Formula I, and an additionalanti-infective medicament.

In still another aspect, a composition of the present inventioncomprises: (a) a member of a family of fluoroquinolones having FormulaII or salts thereof; and (b) an additional anti-infective medicament;wherein

wherein R¹, R³, X, Y, and Z have the meanings as disclosed above; andwherein the composition is capable of inhibiting a growth or survival ofmixed types of microorganisms causing an infection.

In still another aspect, the present invention provides a method fortreating, reducing, ameliorating, or preventing an infection of an ear,a portion of a respiratory system, an eye, or a combination thereof. Themethod comprises administering a composition comprising: (a) afluoroquinolone having Formula I or II; and (b) an additionalanti-infective medicament, to a site of infection to treat, reduce, orameliorate said infection.

In one embodiment, the method comprises topically administering such acomposition. In another embodiment, the method comprises orallyadministering such a composition.

In yet another aspect, said infection comprises infections of an ear, aportion of an upper respiratory system, an eye, or a combinationthereof.

Other features and advantages of the present invention will becomeapparent from the following detailed description and claims.

DETAILED DESCRIPTION

As used herein, the term “lower alkyl” or “lower alkyl group” means aC₁-C₁₅ linear- or branched-chain saturated aliphatic hydrocarbonmonovalent group, which may be unsubstituted or substituted. The groupmay be partially or completely substituted with halogen atoms (F, Cl,Br, or I). Non-limiting examples of lower alkyl groups include methyl,ethyl, n-propyl, 1-methylethyl (or isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl (or t-butyl), and the like. It may be abbreviated as“Alk”.

As used herein, the term “lower alkoxy” or “lower alkoxy group” means aC₁-C₁₅ linear- or branched-chain saturated aliphatic alkoxy monovalentgroup, which may be unsubstituted or substituted. The group may bepartially or completely substituted with halogen atoms (F, Cl, Br, orI). Non-limiting examples of lower alkoxy groups include methoxy,ethoxy, n-propoxy, 1-methylethoxy(isopropoxy), n-butoxy, n-pentoxy,t-butoxy, and the like.

The term “cycloalkyl” or “cycloalkyl group” means a stable aliphaticsaturated 3- to 15-membered monocyclic or polycyclic monovalent radicalconsisting solely of carbon and hydrogen atoms which may comprise one ormore fused or bridged ring(s), preferably a 3- to 7-membered monocyclicrings. Other exemplary embodiments of cycloalkyl groups include 7- to10-membered bicyclic rings. Unless otherwise specified, the cycloalkylring may be attached at any carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitable carbonatom which results in a stable structure. Exemplary cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantyl,tetrahydronaphthyl(tetralin), 1-decalinyl, bicyclo[2.2.2]octanyl,1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and thelike.

As used herein, the term “aryl” or “aryl group” means an aromaticcarbocyclic monovalent or divalent radical. In some embodiments, thearyl group has a number of carbon atoms from 5 to 24 and has a singlering (e.g., phenyl or phenylene), multiple condensed rings (e.g.,naphthyl or anthranyl), or multiple bridged rings (e.g., biphenyl).Unless otherwise specified, the aryl ring may be attached at anysuitable carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Non-limiting examples of aryl groupsinclude phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl,biphenyl, and the like. It may be abbreviated as “Ar”.

The term “heteroaryl” or “heteroaryl group” means a stable aromaticmonocyclic or polycyclic monovalent or divalent radical, which maycomprise one or more fused or bridged ring(s). In some embodiments, theheteroaryl group has 5-24 members, preferably a 5- to 7-memberedmonocyclic or 7- to 10-membered bicyclic radical. The heteroaryl groupcan have from one to four heteroatoms in the ring(s) independentlyselected from nitrogen, oxygen, and sulfur, wherein any sulfurheteroatoms may optionally be oxidized and any nitrogen heteroatom mayoptionally be oxidized or be quaternized. Unless otherwise specified,the heteroaryl ring may be attached at any suitable heteroatom or carbonatom which results in a stable structure and, if substituted, may besubstituted at any suitable heteroatom or carbon atom which results in astable structure. Non-limiting examples of heteroaryls include furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,indolizinyl, azaindolizinyl, indolyl, azaindolyl, diazaindolyl,dihydroindolyl, dihydroazaindoyl, isoindolyl, azaisoindolyl,benzofuranyl, furanopyridinyl, furanopyrimidinyl, furanopyrazinyl,furanopyridazinyl, dihydrobenzofuranyl, dihydrofuranopyridinyl,dihydrofuranopyrimidinyl, benzothienyl, thienopyridinyl,thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl,dihydrobenzothienyl, dihydrothienopyridinyl, dihydrothienopyrimidinyl,indazolyl, azaindazolyl, diazaindazolyl, benzimidazolyl,imidazopyridinyl, benzthiazolyl, thiazolopyridinyl, thiazolopyrimidinyl,benzoxazolyl, benzoxazinyl, benzoxazinonyl, oxazolopyridinyl,oxazolopyrimidinyl, benzisoxazolyl, purinyl, chromanyl, azachromanyl,quinolizinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl,cinnolinyl, azacinnolinyl, phthalazinyl, azaphthalazinyl, quinazolinyl,azaquinazolinyl, quinoxalinyl, azaquinoxalinyl, naphthyridinyl,dihydronaphthyridinyl, tetrahydronaphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl, and the like.

In general, the present invention provides a pharmaceutical compositionand a method for treating, reducing, or ameliorating an infection.

In one aspect, said infection has an etiology that is not readilyascertainable upon presentation.

In another aspect, said infection is caused by mixed types ofmicroorganisms.

In still another aspect, said infection comprises an infection of anear, a portion of a respiratory system, an eye, or a combinationthereof.

In one aspect, said infection is selected from the group consisting ofotitis, sinusitis, nasophrayngitis, orophrayngitis, epiglottitis,laryngotracheitis, bronchitis, bronchiolitis, pneumonia, keratitis,conjunctivitis, blepharitis, hordeolum, phlyctenulosis, endophthalmitis,preseptal and orbital cellulites, dacryocystitis, and combinationsthereof.

In another aspect, a composition of the present invention comprises: (a)at least one member of a family of fluoroquinolones that have Formula Ior salts thereof; and (b) an additional anti-infective medicament;wherein

wherein R¹ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted lower alkyl groups,cycloalkyl groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, and groups that can be hydrolyzed in living bodies;R² is selected from the group consisting of hydrogen, unsubstitutedamino group, and amino groups substituted with one or two lower alkylgroups; R³ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted lower alkyl groups,cycloalkyl groups, unsubstituted lower alkoxy groups, substituted loweralkoxy groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄ arylgroups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, unsubstituted C₅-C₂₄ aryloxy groups, substitutedC₅-C₂ aryloxy groups, unsubstituted C₅-C₂₄ heteroaryloxy groups,substituted C₅-C₂₄ heteroaryloxy groups, and groups that can behydrolyzed in living bodies; X is selected from the group consisting ofhalogen atoms; Y is selected from the group consisting of CH₂, O, S, SO,SO₂, and NR⁴, wherein R⁴ is selected from the group consisting ofhydrogen, unsubstituted lower alkyl groups, substituted lower alkylgroups, and cycloalkyl groups; and Z is selected from the groupconsisting of oxygen and two hydrogen atoms; and wherein the compositionis capable of inhibiting a growth or survival of mixed types ofmicroorganisms causing said infection.

In one aspect, R¹ is selected from the group consisting of hydrogen,C₁-C₅ (or alternatively, C₁-C₃) substituted and unsubstituted alkylgroups, C₃-C₁₀ (or alternatively, C₃-C₅) cycloalkyl groups, C₅-C₁₄ (oralternatively, C₆-C₁₄, or C₅-C₁₀, or C₆-C₁₀) substituted andunsubstituted aryl groups, C₅-C₁₄ (or alternatively, C₆-C₁₄, or C₅-C₁₀,or C₆-C₁₀) substituted and unsubstituted heteroaryl groups, and groupsthat can be hydrolyzed in living bodies. In one embodiment, R¹ isselected from the group consisting of C₁-C₅ (or alternatively, C₁-C₃)substituted and unsubstituted alkyl groups.

In another aspect, R² is selected from the group consisting ofunsubstituted amino group and amino groups substituted with one or twoC₁-C₅ (or alternatively, C₁-C₃) alkyl groups.

In still another aspect, R³ is selected from the group consisting ofhydrogen, C₁-C₅ (or alternatively, C₁-C₃) substituted and unsubstitutedalkyl groups, C₃-C₁₀ (or alternatively, C₃-C₅) cycloalkyl groups, C₁-C₅(or alternatively, C₁-C₃) substituted and unsubstituted alkoxy groups,C₅-C₁₄ (or alternatively, C₆-C₁₄, or C₅-C₁₀, or C₆-C₁₀) substituted andunsubstituted aryl groups, C₅-C₁₄ (or alternatively, C₆-C₁₄, or C₅-C₁₀,or C₆-C₁₀) substituted and unsubstituted heteroaryl groups, and C₅-C₁₄(or alternatively, C₆-C₁₄, or C₅-C₁₀, or C₆-C₁₀) substituted andunsubstituted aryloxy groups. In one embodiment, R³ is selected from thegroup consisting of C₃-C₁₀ (or alternatively, C₁-C₅) cycloalkyl groups.

In yet another aspect, X is selected from the group consisting of Cl, F,and Br. In one embodiment, X is Cl. In another embodiment, X is F.

In a further aspect, Y is CH₂ and Z comprises two hydrogen atoms.

In still another aspect, Y is NH, Z is O, and X is Cl.

Some non-limiting members of the family of compounds having Formula Iare shown in Table 1. Other compounds of the family not listed in Table1 are also suitable in selected situations.

TABLE 1 Some Selected Fluoroquinolones Compound R¹ R² R³ X Y Z 1 H H CH₃Cl CH₂ 2 H 2 H NH₂ CH₃ Cl CH₂ 2 H 3 H NH₂ cyclopropyl Cl CH₂ 2 H 4 HNH(CH₃) cyclopropyl Cl CH₂ 2 H 5 H N(CH₃)₂ cyclopropyl Cl CH₂ 2 H 6 CH₃NH₂ cyclopropyl Cl CH₂ 2 H 7 C₂H₅ NH₂ cyclopropyl Cl CH₂ 2 H 8 H NH₂cyclopropyl F CH₂ 2 H 9 H NH₂ cyclopropyl Br CH₂ 2 H 10 H NH(C₃H₅)cyclopropyl Cl CH₂ 2 H 11 H NH(C₃H₅) cyclopropyl F CH₂ 2 H 12 H NH₂cyclopentyl Cl CH₂ 2 H 13 H NH₂ cyclopropyl Cl CH₂ O 14 H NH₂cyclopropyl F CH₂ O 15 H NH₂ cyclopropyl Br CH₂ O 16 H NH₂ cyclopropylCl CH(C₃H₅) O 17 CH₃ NH₂ cyclopropyl Cl CH₂ O 18 CH₃ NH(CH₃) cyclopropylCl CH₂ O 19 CH₃ N(CH₃)₂ cyclopropyl Cl CH₂ O 20 CH₃ NH(C₃H₅) cyclopropylCl CH₂ O 21 CH₃ NH(C₃H₅) cyclopropyl Cl CH₂ O 22 CH₃ N(CH₃)(C₂H₅)cyclopropyl Cl CH₂ O 23 H NH₂ cyclopropyl Cl NH O 24 CH₃ NH(CH₃)cyclopropyl Cl NH O 25 H 2H cyclopropyl Cl NH O

In one embodiment, the fluoroquinolone carboxylic acid included in acomposition of the present invention has Formula III.

In another embodiment, the fluoroquinolone carboxylic acid included in acomposition of the present invention has Formula IV, V, or VI.

In still other embodiments, the fluoroquinolone carboxylic acid includedin a composition of the present invention has Formula VII or VIII.

In still another aspect, a composition of the present inventioncomprises an enantiomer of one of the compounds having Formula I, II, orIII.

In still another aspect, a composition of the present inventioncomprises a mixture of enantiomers of one of the compounds havingFormula I, II, or III.

In a further aspect, the additional anti-infective medicament isselected from the group consisting of an antibacterial agent other thanthe quinolones having Formulae II, III, IV, V, VI, VII, and VIII; anantifungal agent; an antiviral agent; an antiprotozoal agent; andcombinations thereof.

In another aspect, the additional antibacterial agent other than thequinolones having Formulae I, II, III, IV, V, VI, VII, and VIIIcomprises another quinolone.

In still another aspect, said another quinolone is selected from thegroup consisting of cinoxacin, ciprofloxacin, clinafloxacin, difloxacin,enoxacin, fleroxacin, gatitloxacin, grepafloxacin, levotloxacin,lometloxacin, miloxacin, moxifloxacin, nadifloxacin, norfloxacin,ofloxacin, pazutloxacin, pefloxacin, sitafloxacin, sparfloxacin,temafloxacin, tosufloxacin, trovafloxacin, mixtures thereof, andcombinations thereof.

In yet another aspect, said another quinolone has a MIC₉₀ value for aGram-negative bacterium that is lower than that of the fluoroquinolonehaving Formula I, II, III, IV, V, VI, VII, or VIII for the samebacterium, said fluoroquinolone being included in the composition. MIC₉₀is the minimum concentration of the active compound required to inhibitninety percent of the growth of a specified pathogen, in μg/ml.

Non-limiting examples of antibacterial agents other than the quinoloneshaving antibacterial agent other than the quinolones having Formulae I,II, III, IV, V, VI, VII, and VIII include biologically-derivedantibacterial agents such as aminoglycosides (e.g., amikacin, apramycin,arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin,fortimicin(s), gentamicin, isepamicin, kanamycin, micronomicin,neomycin, neomycin undecylenate, netilmicin, paromomycin, ribostamycin,sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin),amphenicols (e.g., azidamfenicol, chloramphenicol, florfenicol,thiamphenicol), ansamycins (e.g., rifamide, rifampin, rifamycin sv,rifapentine, rifaximin), β-lactams (e.g., carbacephems (e.g.,loracarbef), carbapenems (e.g., biapenem, imipenem, meropenem,panipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole,cefatrizine, cefazedone, cefazolin, cefcapene pivoxil, cefclidin,cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime,cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam,cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil,cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole,ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam,cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine,cephalosporin, cephalothin, cephapirin sodium, cephradine,pivcefalexin), cephamycins (e.g., cefbuperazone, cefinetazole,cefininox, cefotetan, cefoxitin), monobactams (e.g., aztreonam,carumonam, tigemonam), oxacephems, flomoxef, moxalactam), penicillins(e.g., amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin,apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin,benzylpenicillinic acid, benzylpenicillin sodium, carbenicillin,carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin,epicillin, fenbenicillin, floxacillin, hetacillin, lenampicillin,metampicillin, methicillin sodium, mezlocillin, nafcillin sodium,oxacillin, penamecillin, penethamate hydroiodide, penicillin Gbenethamine, penicillin G benzathine, penicillin G benzhydrylamine,penicillin G calcium, penicillin G hydrabamine, penicillin G potassium,penicillin G procaine, penicillin N, penicillin O, penicillin V,penicillin V benzathine, penicillin V hydrabamine, penimepicycline,phenethicillin potassium, piperacillin, pivampicillin, propicillin,quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin,ticarcillin), ritipenem, lincosamides (e.g., clindamycin, lincomycin),macrolides (e.g., azithromycin, carbomycin, clarithromycin,dirithromycin, erythromycin, erythromycin acistrate, erythromycinestolate, erythromycin glucoheptonate, erythromycin lactobionate,erythromycin propionate, erythromycin stearate, josamycin, leucomycins,midecamycins, miokamycin, oleandomycin, primycin, rokitamycin,rosaramicin, roxithromycin, spiramycin, troleandomycin), polypeptides(e.g., amphomycin, bacitracin, capreomycin, colistin, enduracidin,enviomycin, fusafungine, gramicidin s, gramicidin(s), mikamycin,polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton,tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin,virginiamycin, zinc bacitracin), tetracyclines (e.g., apicycline,chlortetracycline, clomocycline, demeclocycline, doxycycline,guamecycline, lymecycline, meclocycline, methacycline, minocycline,oxytetracycline, penimepicycline, pipacycline, rolitetracycline,sancycline, tetracycline), cycloserine, mupirocin, and tuberin.

Non-limiting examples of synthetic antibacterial agents include2,4-diaminopyrimidines (e.g., brodimoprim, tetroxoprim, trimethoprim),nitrofurans (e.g., furaltadone, furazolium chloride, nifuradene,nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol,nitrofuirantoin), quinolones and analogs (e.g., cinoxacin,ciprotloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin,flumequine, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin,miloxacin, moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin,ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid,piromidic acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin,tosufloxacin, trovafloxacin, sulfonamides (e.g., acetylsulfamethoxypyrazine, benzylsulfamide, chloramines B, chloramines T,dichloramine T, n²-formylsulfisomidine, n⁴-β-D-glucosylsulfanilamide,mafenide, 4′-(methylsulfamoyl)sulfanilanilide, noprylsulfamide,phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine,succinylsulfathiazole, sulfabenzamide, sulfacetamide,sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine,sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,sulfamethoxazole, sulfamethoxypyridazine, sulfametrole,sulfamidochrysoidine, sulfamoxole, sulfanilamide,4-sulfanilamidosalicylic acid, n⁴-sulfanilylsulfanilamide,sulfanilylurea, N-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea,sulfatolamide, sulfisomidine, sulfisoxazole) sulfones (e.g., acedapsone,acediasulfone, acetosulfone sodium, dapsone, diathymosulfone,glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid,p-sulfanilylbenzylamine, sulfoxone sodium, thiazolsulfone), clofoctol,hexedine, methenamine, methenamine anhydromethylene citrate, methenaminehippurate, methenamine mandelate, methenamine sulfosalicylate,nitroxoline, taurolidine, and xibomol. In one embodiment, a compostionof the present invention comprises an anti-infective agent selected fromthe group consisting of cinoxacin, ciprofloxacin, clinafloxacin,difloxacin, enoxacin, fleroxacin, flumequine, gatifloxacin,grepafloxacin, levofloxacin, lomefloxacin, miloxacin, moxifloxacin,nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid,pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, rosoxacin,rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, and trovafloxacin.

Non-limiting examples of antiviral agents include rifampin, ribavirin,pleconaryl, cidofovir, acyclovir, pencyclovir, gancyclovir,valacyclovir, famciclovir, foscarnet, vidarabine, amantadine, zanamivir,oseltamivir, resquimod, adenosine arabinoside, cytosine arabinoside,antiproteases, PEGylated interferon (Pegasys™), anti HIV proteases (e.g.lopinivir, saquinivir, amprenavir, HIV fusion inhibitors, nucleotide HIVRT inhibitors (e.g., AZT, lamivudine, abacavir), non-nucleotide HIV RTinhibitors, doconosol, interferons, hutylated hydroxytoluene (BHT), andhypericin.

Non-limiting examples of biologically-derived antifungal agents includepolyenes (e.g., amphotericin B, candicidin, dermostatin, filipin,fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin,nystatin, pecilocin, perimycin), azaserine, griseofulvin, oligomycins,neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin, and viridin.

Non-limiting examples of synthetic antifungal agents include allylamines(e.g., butenafine, naftifine, terbinafine), imidazoles (e.g.,bifonazole, butoconazole, chlordantoin, chlormidazole, cloconazole,clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole,isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole,oxiconazole nitrate, sertaconazole, sulconazole, tioconazole),thiocarbamates (e.g., tolciclate, tolindate, tolnaftate), triazoles(e.g., fluconazole, itraconazole, saperconazole, terconazole),acrisorcin, amorolfine, biphenamine, bromosalicylchloranilide,buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxyquin,coparaffinate, diamthazole dihydrochloride, exalamide, flucytosine,halethazole, hexetidine, loflucarban, nifuratel, potassium iodide,propionic acid, pyrithione, salicylanilide, sodium propionate,sulbentine, tenonitrozole, triacetin, ujothion, undecylenic acid, andzinc propionate.

Non-limiting examples of antiprotozoal agents include polymycin Bsulfate, bacitracin zinc, neomycine sulfate (e.g., Neosporin®),imidazoles (e.g., clotrimazole, miconazole, ketoconazole), aromaticdiamidines (e.g., propamidine isethionate, brolene), polyhexamethylenebiguanide (“PHMB”), chlorhexidine, pyrimethamine (Daraprim®),sulfadiazine, folinic acid (leucovorin), clindamycin, andtrimethoprim-sulfamethoxazole.

The amount of a fluoroquinolone compound having Formula I, II, III, IV,V, VI, VII, or VIII that is incorporated into a composition of thepresent invention is not critical; the concentration should be within arange sufficient to permit ready application of the composition to theaffected tissue area in an amount which will deliver the desired amountof compound to the desired treatment site and to provide the desiredtherapeutic effect. In some embodiments of the present invention,compositions comprise a fluoroquinolone having Formula I, II, III, IV,V, VI, VII, or VIII in a concentration in a range from about 0.0001% to10% by weight (or alternatively, from about 0.001% to about 5%, or fromabout 0.01% to about 5%, or from about 0.01% to about 2%, or from about0.01% to about 1%, or from about 0.01% to about 0.7%, or from about0.01% to about 0.5%, by weight).

In another aspect, the concentration of said additional anti-infectivemedicament in a composition of the present invention can be in the rangefrom about 0.0001% to 10% by weight (or alternatively, from about 0.001%to about 5%, or from about 0.01% to about 5%, or from about 0.01% toabout 2%, or from about 0.01% to about 1%, or from about 0.01% to about0.7%, or from about 0.01% to about 0.5%, by weight).

In still another aspect, a composition of the present invention furthercomprises a pharmaceutically acceptable carrier.

A fluoroquinolone compound and an additional anti-infective medicamentthat are disclosed herein can be formulated into a pharmaceuticalcomposition for topical, oral, or systemic administration for thetreatment, reduction, amelioration, or prevention of an. In anembodiment, such infection comprises an infection of an ear, a portionof a respiratory system, an eye, or a combination thereof. Such acomposition comprises a fluoroquinolone compound having Formula I, II,III, IV, V, VI, VII, or VIII, an additional anti-infective medicament,and a pharmaceutically acceptable carrier for the administration, whichcarrier can be determined by a person having skill in the art ofpharmaceutical formulation for the applications disclosed above. Forexample, various pharmaceutically acceptable carriers known in the artcan be used to formulate a solution, suspension, dispersion, ointment,gel, capsule, or tablet. A fluoroquinolone compound having Formula I,II, III, IV, V, VI, VII, or VIII disclosed herein is particularlysuitable for a treatment, reduction, amelioration, or prevention ofinfections of an ear, a portion of a respiratory system, an eye, or acombination thereof, which infections are caused by bacteria, fungi,viruses, protozoans, or combinations thereof, including, but not beinglimited to, the bacteria, fungi, viruses, and protozoans disclosedabove. In one embodiment, such infections are caused by mixedmicroorganisms comprising at least one bacterium. In another embodiment,such a fluoroquinolone and an additional anti-infective medicament oragent are formulated into a solution, ointment, suspension, dispersion,or gel.

In one embodiment, a topical composition of the present inventioncomprises an aqueous solution or suspension. Typically, purified ordeionized water is used. The pH of the composition is adjusted by addingany physiologically and otically acceptable pH adjusting acids, bases,or buffers to within the range of about 3 to about 8.5 (oralternatively, or from about 4 to about 7.5, or from about 4 to about6.5, or from about 5 to about 6.5). Examples of acids include acetic,boric, citric, lactic, phosphoric, hydrochloric, and the like, andexamples of bases include sodium hydroxide, sodium phosphate, sodiumborate, sodium citrate, sodium acetate, sodium lactate, tromethamine,THAM (trishydroxymethylamino-methane), and the like. Salts and buffersinclude citrate/dextrose, sodium bicarbonate, ammonium chloride andmixtures of the aforementioned acids and bases. pH buffers areintroduced into the composition to maintain a stable pH and to improveproduct tolerance by the user. In some embodiments, the pH is in therange from about 4 to about 7.5. Biological buffers for various pHs areavailable, for example, from Sigma-Aldrich. A composition of the presentinvention can have a viscosity in the range from about 5 to about100,000 centipoise (“cp”) or mPa·s (or alternatively, from about 10 toabout 50,000, or from about 10 to about 20,000, or from about 10 toabout 10,000, or from about 10 to about 1,000, or from about 100 toabout 10,000, or from about 100 to about 20,000, or from about 100 toabout 50,000 or from about 500 to about 10,000, or from about 500 toabout 20,000 cp).

In another embodiment, a topical composition of the present inventioncomprises an ointment, emulsion or cream (such as oil-in-wateremulsion), or gel.

Ointments generally are prepared using either (1) an oleaginous base;i.e., one consisting of fixed oils or hydrocarbons, such as whitepetrolatum or mineral oil, or (2) an absorbent base; i.e., oneconsisting of an anhydrous substance or substances which can absorbwater, for example anhydrous lanolin. Customarily, following formationof the base, whether oleaginous or absorbent, the active ingredient(compound) is added to an amount affording the desired concentration.

Creams are oil/water emulsions. They consist of an oil phase (internalphase), comprising typically fixed oils, hydrocarbons, and the like,such as waxes, petrolatum, mineral oil, and the like, and an aqueousphase (continuous phase), comprising water and any water-solublesubstances, such as added salts. The two phases are stabilized by use ofan emulsifying agent, for example, a surface active agent, such assodium lauryl sulfate, hydrophilic colloids, such as acacia colloidalclays, veegum, and the like. Upon formation of the emulsion, the activeingredient (compound) customarily is added in an amount to achieve thedesired concentration.

Gels comprise a base selected from an oleaginous base, water, or anemulsion-suspension base. To the base is added a gelling agent whichforms a matrix in the base, increasing its viscosity. Examples ofgelling agents are hydroxypropyl cellulose, acrylic acid polymers, andthe like. Customarily, the active ingredient (compound) is added to theformulation at the desired concentration at a point preceding additionof the gelling agent.

Moreover, a topical composition of the present invention can contain oneor more of the following: preservatives, surfactants, adjuvantsincluding additional medicaments, antioxidants, tonicity adjusters,viscosity modifiers, and the like.

Preservatives may be used to inhibit microbial contamination of theproduct when it is dispensed in single or multidose containers, and caninclude: quaternary ammonium derivatives, (benzalkonium chloride,benzylammonium chloride, cetylmethyl ammonium bromide, cetylpyridiniumchloride), benzethonium chloride, organomercury compounds (Thimerosal,phenylmercury acetate, phenylmercury nitrate), methyl and propylp-hydroxy-benzoates, betaphenylethyl alcohol, benzyl alcohol,phenylethyl alcohol, phenoxyethanol, and mixtures thereof. Thesecompounds are used at effective concentrations, typically from about0.005% to about 5% (by weight), depending on the preservative orpreservatives selected. The amount of the preservative used should beenough so that the solution is physically stable; i.e., a precipitate isnot formed, and antibacterially effective.

The solubility of the components, including a fluoroquinolone havingFormula I, II, III, IV, V, VI, VII, or VIII of the present compositionsmay be enhanced by a surfactant or other appropriate co-solvent in thecomposition or solubility enhancing agents like cyclodextrins such ashydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosylderivatives of α-, β-, and γ-cyclodextrin. In one embodiment, thecomposition comprises 0.1% to 20% hydroxypropyl-β-cyclodextrin;alternatively, 1% to 15% (or 2% to 10%) hydroxypropyl-β-cyclodextrin.Co-solvents include polysorbates (for example, polysorbate 20, 60, and80), polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic® F68,F84, F127, and P103), cyclodextrin, fatty-acid triglycerides, glycerol,polyethylene glycol, other solubility agents such as octoxynol 40 andtyloxapol, or other agents known to those skilled in the art andmixtures thereof. The amount of solubility enhancer used will depend onthe amount of fluoroquinolone in the composition, with more solubilityenhancer used for greater amounts of fluoroquinolones. Typically,solubility enhancers are employed at a level of from 0.01% to about 20%(alternatively, from about 0.1% to about 10%, from about 0.1% to about5%, or from about 0.1% to about 2%) by weight depending on theingredient.

The use of viscosity enhancing agents to provide the compositions of theinvention with viscosities greater than the viscosity of simple aqueoussolutions may be desirable to increase absorption of the activecompounds by the target tissues or to increase the retention time in theear. Such viscosity enhancing agents include, for example, polyvinylalcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxypropyl cellulose or other agents know to those skilled in theart. Such agents are typically employed at a level of from about 0.01%to about 10% (alternatively, from about 0.1% to about 5%, or from about0.1% to about 2%) by weight.

Suitable surfactants include polyvinyl pyrolidone, polyvinyl alcohol,polyethylene glycol, ethylene glycol, and propylene glycol. Othersurfactants are polysorbates (such as polysorbate 80 (polyoxyethylenesorbitan monooleate), polysorbate 60 (polyoxyethylene sorbitanmonostearate), polysorbate 20 (polyoxyethylene sorbitan monolaurate),commonly known by their trade names of Tween® 80, Tween® 60. Tween® 20),poloxamers (synthetic block polymers of ethylene oxide and propyleneoxide, such as those commonly known by their trade names of Pluronic®;e.g., Pluronic® F127 or Pluronic® F108)), or poloxamines (syntheticblock polymers of ethylene oxide and propylene oxide attached toethylene diamine, such as those commonly known by their trade names ofTetronic®: e.g., Tetronic® 1508 or Tetronic® 908, etc., other nonionicsurfactants such as Brij®, Myrj®, and long chain fatty alcohols (i.e.,oleyl alcohol, stearyl alcohol, myristyl alcohol, docosohexanoylalcohol, etc.) with carbon chains having about 12 or more carbon atoms(e.g., such as from about 12 to about 24 carbon atoms). The surfactanthelps a topical formulation to spread on the surface of narrow passages.

It is often that an infection is followed by inflammation. Therefore, inanother aspect, a composition of the present invention further comprisesan anti-inflammatory agent. Anti-inflammatory agents include thewell-known glucocorticosteroids and the non-steroidal anti-inflammatorydrugs (“NSAIDs”).

Non-limiting examples of the glucocorticosteroids are:21-acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortarnate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone henetonide, triamcinolonehexacetonide, their physiologically acceptable salts, combinationsthereof, and mixtures thereof.

The preferred glucocorticoids for otic use include dexamethasone,loteprednol, rimexolone, prednisolone, fluorometholone, hydrocortisone,and their derivatives. The preferred glucocorticoids for nasal useinclude mometasone, fluticasone, beclomethasone, flunisolide,triamcinolone, budesonide, and their derivatives.

Non-limiting examples of the NSAIDs are: aminoarylcarboxylic acidderivatives (e.g., enfenamic acid, etofenamate, flufenamic acid,isonixin, meclofenamic acid, mefenamic acid, niflumic acid,talnitlumate, terofenamate, tolfenamic acid), arylacetic acidderivatives (e.g., aceclofenac, acemetacin, alclofenac, amfenac,amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac,diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac,glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac,metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin,sulindac, tiaramide, tolmetin, tropesin, zomepirac), arylbutyric acidderivatives (e.g., bumadizon, butibufen, fenbufen, xenbucin),arylcarboxylic acids (e.g., clidanac, ketorolac, tinoridine),arylpropionic acid derivatives (e.g., alminoprofen, benoxaprofen,bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen,flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen,naproxen, oxaprozin, piketoprolen, pirprofen, pranoprofen, protizinicacid, suprofen, tiaprofenic acid, ximoprofen, zaltoprofen), pyrazoles(e.g., difenamizole, epirizole), pyrazolones (e.g., apazone,benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone,phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone,thiazolinobutazone), salicylic acid derivatives (e.g., acetaminosalol,aspirin, benorylate, bromosaligenin, calcium acetylsalicylate,diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate,imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholinesalicylate, 1-naphthyl salicylate, olsalazine, parsalmide, phenylacetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-aceticacid, salicylsulfuric acid, salsalate, sulfasalazine),thiazinecarboxamides (e.g., ampiroxicam, droxicam, isoxicam, lornoxicam,piroxicam, tenoxicam), E-acetamidocaproic acid,S-(5′-adenosyl)-L-methionine, 3-amino-4-hydroxybutyric acid, amixetrine,bendazac, benzydamine, α-bisabolol, bucolome, difenpiramide, ditazol,emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol,paranyline, perisoxal, proquazone, superoxide dismutase, tenidap,zileuton, their physiologically acceptable salts, combinations thereof,and mixtures thereof. In one embodiment, the NSAID is diclofenac,furbiprofen, or ketorolac.

Other non-steroidal anti-inflammatory agents include the cyclooxygenasetype II selective inhibitors, such as celecoxib, and etodolac; plateletactivating factor (“PAF”) antagonists, such as apafant, bepafant,minopafant, nupafant, and modipafant; phosphodiesterase (“PDE”) IVinhibitors, such as ariflo, torbafylline, rolipram, filaminast,piclamilast, cipamfylline, and roflumilast; inhibitors of cytokineproduction, such as inhibitors of the NF-κB transcription factor; orother anti-inflammatory agents known to those skilled in the art.

The concentrations of the anti-inflammatory agents contained in thecompositions of the present invention will vary based on the agent oragents selected and the type of inflammation being treated. Theconcentrations will be sufficient to reduce inflammation in the targetedtissues following topical application of the compositions to thosetissues. Such concentrations are typically in the range from about0.0001 to about 3% by weight (or alternatively, from about 0.01 to about2%, or from about 0.05% to about 1%, by weight).

Bacterial pathogens that have been isolated from cases of ear infectioninclude Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcuspneumoniae, Streptococcus pyrogenes, Streptococcus faecalis, Haemophilusinfluenzae, Moraxella catarahalis, Escherichia coli, Proteus species,Klebsiella species, and Enterococcus species. Several of these speciesfrom the isolates have been found to be resistant to a number ofantimicrobial drugs. For example, a published study ofantimicrobial-resistant pathogens in middle-ear fluid of children withacute otitis media shows that thirty percent of the S. pneumoniaeisolates were intermediately or fully resistant, and eight percent fullyresistant, to penicillin; ten percent of the isolates were resistant toamoxicillin or amoxicillin-clavulanate. M. R. Jacobs et al.,Antimicrobial Agents and Chemotherapy, Vol. 42, No. 3, 589 (1998). Thesame study shows that thirty percent of H. influenzae isolates producedβ-lactamase, and thus, were expected to be resistant to penicillin.

Bacterial pathogens that have been isolated from cases of upperrespiratory infection include Staphylococcus aureus, Staphylococcusepidermidis, Streptococcus pneumoniae, Streptococcus pyrogenes,Haemophilus influenzae, Peptostreptococcus species, and Bacteroidesspecies. Some of these strains have been found to be resistant tocommonly used antibiotics, as mentioned above.

Anti-bacterial activity of the compound having Formula IV was testedagainst several Gram-negative reference bacteria strains and compared tothe anti-bacterial activity of three commercially available antibiotics(nadifloxacin, ofloxacin, and sparfloxacin). The results are shown inTable 2 as MIC₉₀ values (minimum concentration of the active compoundrequired to inhibit ninety percent of the growth of a specifiedpathogen, in μg/ml).

TABLE 2 Comparison of In vitro Anti-bacterial Activity of CompoundHaving Formula IV, Nadifloxacin, Ofloxacin, and Sparfloxacin AgainstSome Gram-Negative Bacteria MIC₉₀ (μg/ml) Compound Having Strain FormulaIV Nadifloxacin Ofloxacin Sparfloxacin Escherichia coli 0.1 0.2 0.050.012 (O-1) Klebsiella 0.024 0.1 0.024 0.012 pneumoniae (IFO 13541)Salmonella 0.05 0.2 0.05 0.012 typhimurium (TD) Shigella flextzeri 0.0060.006 0.006 0.006 (2b) Enterobacter 0.39 1.56 0.2 0.1 aerogenes (IFO13534) Serratia 0.2 1.56 0.1 0.2 marcenscens (NHL) Proteus mirabilis 0.10.1 0.05 0.1 (IFO 13300) Proteus rettgeri 0.39 0.39 0.2 0.2Acinetobacter 0.39 0.78 0.39 0.024 calcoaceticus (IFO 12552) Pseudomonas1.56 3.13 1.56 0.78 aeruginosa (IFO 13736) Pseudomonas 1.56 6.25 3.130.78 aeruginosa (ATCC 27853)

Anti-bacterial activity of the compound having Formula IV was testedagainst several Gram-positive reference bacteria strains and compared tothe anti-bacterial activity of three commercially available antibiotics(nadifloxacin, ofloxacin, and sparfloxacin). The results are shown inTable 3 as MIC₉₀ values.

TABLE 3 Comparison of In vitro Anti-bacterial Activity of CompoundHaving Formula IV, Nadifloxacin, Ofloxacin, and Sparfloxacin AgainstSome Gram-Positive Bacteria MIC₉₀ (μg/mL) Compound Having Strain FormulaIV Nadifloxacin Ofloxacin Sparfloxacin Bacillis subtilis 0.012 0.0060.05 0.024 (ATCC 6633) Staphylococcus 0.05 0.05 0.39 0.1 aureus (ATCC25933) Staphylococcus 0.012 0.024 0.2 0.024 aureus (FDA 209P)Staphylococcus 0.006 0.024 0.2 0.05 aureus (Smith) Staphylococcus 0.050.1 0.78 0.2 epidermidis (ATCC 12228) Sarcina lutea 0.1 0.39 3.13 1.56(ATCC 9341) Streptococcus 0.1 0.78 1.56 0.78 faecalis (WO 12964)Streptococcus 0.2 0.78 1.56 0.39 faecalis (ATCC 29212) Streptococcus 0.10.78 0.78 0.39 pyogenes (Cook) Streptococcus 0.1 0.1 0.39 0.2 pyogenes(IID 698) Streptococcus 0.1 0.78 1.56 0.39 pneumoniae (IID 553)Streptococcus 0.2 0.78 1.56 0.39 pneniae (IID 554)

Anti-bacterial activity of the compound having Formula IV was testedagainst some methicillin-resistant Staphylococcus aureus bacteriastrains and compared to the anti-bacterial activity of threecommercially available antibiotics (nadifloxacin, ofloxacin, andsparfloxacin). The results are shown in Table 4 as MIC₉₀ values.

TABLE 4 Comparison of In vitro Anti-bacterial Activity of CompoundHaving Formula IV, Nadifloxacin, Ofloxacin, and Sparfloxacin AgainstSome Methicillin-Resistant Staphylococcus aureus Isolates MIC₉₀ (μg/mL)Compound Having Strain Formula IV Nadifloxacin Otloxacin SparfloxacinStaphylococcus 0.012 0.006 0.05 0.024 aureus (ATCC 33591) Staphylococcus0.05 0.05 0.39 0.1 aureus (ATCC 33592) Staphylococcus 0.012 0.024 0.20.024 aureus (ATCC 33593) Staphylococcus 0.006 0.024 0.2 0.05 aureus(No. 395) Staphylococcus 0.05 0.1 0.78 0.2 aureus (No. 415)Staphylococcus 0.1 0.39 3.13 1.56 aureus (No. 419) Staphylococcus 0.10.78 1.56 0.78 aureus (No. 420) Staphylococcus 0.2 0.78 1.56 0.39 aureus(No. 421)

Anti-bacterial activity of the compound having Formula IV was testedagainst selected anaerobic reference bacteria and compared to theanti-bacterial activity of three commercially available antibiotics(nadifloxacin, ofloxacin, and sparfloxacin). The results are shown inTable 5 as MIC₉₀ values.

TABLE 5 Comparison of In vitro Anti-bacterial Activity of CompoundHaving Formula IV, Nadifloxacin, Ofloxacin, and Sparfloxacin AgainstSome Common Anaerobic Bacteria MIC₉₀ (μg/mL) Compound Having FormulaStrain IV Nadifloxacin Ofloxacin Sparfloxacin Clostridium 0.2 0.2 0.780.39 perfringens (KZ 210) Peptostreptococcus 0.2 0.39 0.78 0.78 micros(GIFU 7824) Peptostreptococcus 0.05 0.2 0.39 0.1 magnum (GAI 0664)Propionibacterium 0.2 0.2 0.78 0.39 acnes (GAI 5419) Propionibacterium0.2 0.2 0.78 0.39 acnes (ATCC 6919) Propionibacterium 0.39 0.78 1.560.78 acnes (ATCC 11828) Bacteroides 0.1 1.56 1.56 0.78 fragillis (GAI0675) Bacteroides 0.2 1.56 3.13 0.78 thetaiotuomicron (GAI 0659)Bacteroides 0.1 0.78 3.13 0.78 vulgatus (GAI 0673) Veillonella 0.1 0.780.39 0.2 parvula (GAI 5602)

Anti-bacterial activity of the compound having Formula IV was testedagainst some ophthalmologic clinical bacteria isolates and compared tothe anti-bacterial activity of three commercially available antibiotics(nadifloxacin, ofloxacin, and ciprofloxacin). As disclosed above, mostof these bacteria strains are also relevant to infections of the ear andupper respiratory tract. The results are shown in Table 6 as MIC₉₀values.

TABLE 6 Comparison of In vitro Anti-bacterial Activity of CompoundHaving Formula IV, Nadifloxacin, Ofloxacin, and Ciprofloxacin AgainstSome Clinical Bacteria Isolates MIC₉₀ (μg/mL) Compound Having StrainFormula IV Norfloxacin Ofloxacin Ciporfloxacin Gram-negative Moraxellaspecies 0.13 0.25 0.13 0.06 Pseudotnonas 4 4 4 0.5 aeruginosaHaemophilus ≦0.06 ≦0.06 ≦0.06 ≦0.06 influenzae Gram-positiveStaphylococcus 1 >128 32 64 aureus Coagulase-negative 0.5 128 8 16Staphylococcus Streptococcus 0.13 8 pneumoniae Corynebacterium 2 16 32 8species Propionibacterium 0.25 4 1 0.5 acnes Antibiotic-resistantOrganisms Ofloxacin-resistant 16 128 64 32 Enterobacteriaceae Ofloxacin-resistant 8 >128 >128 >128 Staphylococcus aureus Gentamycin-resistant 4128 128 128 Staphylococcus aureus Gentamycin-resistant 32 128 64 32Pseudomonas aeruginosa Penicillin-resistant 0.13 8 2 1 Streptococcuspneumoniae

The results show that the compound having Formula IV is effectiveagainst bacteria, including some antibiotic-resistant strains, whichhave been found in cases of infection of the eye, ear, or upperrespiratory tract. Although the applicants do not wish to be bound byany particular theory, they believe that the unique moieties on thefluoroquinolones disclosed herein provide their advantageousantibacterial property and are effective for the treatment, reduction,amelioration, or prevention of infection of the ear, including otitisexterna and otitis media, and infection of the upper respiratory tract,including sinusitis, nasopharyngitis, and oropharyngitis.

The following examples are provided to further illustrate non-limitingcompositions of the present invention, and methods of preparing suchcomposition, for the treatment, reduction, amelioration, or preventionof infections.

Example 1 Antibacterial Solution

Ingredient Amount (% by weight) Compound having Formula IV 0.2Tobramycin 0.3 Hydroxypropylmethyl cellulose (“HPMC”) 0.5 Benzakoniumchloride (“BAK”) 0.01 Pluronic ® F127 0.1 EDTA 0.1 NaCl 0.25 Phosphatebuffer (0.05M, pH = 5.0) q.s. to 100

An appropriate proportion (shown in the above table) of Pluronic® F127is added to phosphate buffer in a sterilized stainless steel jacketedvessel equipped with a stirring mechanism, at a temperature in the rangefrom 50 to 60° C. The resulting buffer solution is heated to 61 to 75°C. At a temperature of about 66° C., an appropriate amount of BAK isadded to the buffer solution while mixing three to ten minutes. At atemperature of 75° C., appropriate amounts of the compound havingFormula IV and tobramycin are added to the contents of the vessel over aperiod of three to fifteen minutes while mixing continues. EDTA and NaClare then added to the mixture while mixing continues for five to fifteenmore minutes at 75° C. The resulting mixture is cooled to 25 to 30′ C.The final composition is packaged in appropriate containers.

Example 2 Antibacterial Solution

A procedure similar to that of Example 1 is used to produce thissolution.

Ingredient Amount (% by weight) Compound having Formula IV 0.35Trimethoprim 0.3 Mannitol 4.5 Benzakonium chloride (“BAK”) 0.005Polysorbate 80 0.1 EDTA 0.05 Sodium acetate 0.03 Acetic acid 0.04Purified water q.s. to 100

Example 3 Antibacterial and Anti-Inflammatory Solution

A procedure similar to that of Example 1 is used to produce thissolution having the following composition.

Ingredient Amount (% by weight) Compound having Formula IV 0.2 Neomycin0.25 Dexamethasone 0.1 Hydroxypropylmethyl cellulose 0.5 (“HPMC”)Alexidine 0.01 Brij ® surfactant 0.1 EDTA 0.1 Citrate buffer (0.02Msodium q.s. to 100 citrate, pH = 5)

Example 4 Antibacterial, Anti-Fungal, and Anti-Inflammatory Solution

A procedure similar to that of Example 1 is used to produce thissolution having the following composition.

Ingredient Amount (% by weight) Compound 8 of Table 1 0.3 Chlormidazole0.2 Colecoxib 0.15 Propylene glycol 0.5 Alexidine 0.01 Tyloxapol 0.1EDTA 0.1 Citrate buffer (0.02M sodium q.s. to 100 citrate, pH = 5)

Example 5 Antibacterial, Antiviral, and Anti-Inflammatory Suspension

A procedure similar to that of Example 1 is used to produce thissolution having the following composition.

Ingredient Amount (% by weight) Compound having Formula VI 0.3 Rifampin0.25 Triamcinolone, micronized USP 0.2 Hydroxyethyl cellulose 0.25 BAK0.01 Tyloxapol 0.05 EDTA 0.01 NaCl 0.3 Na₂SO₄ 1.2 Sulfuric acid and/orNaOH q.s. for pH adjustment to 5.5 Citrate buffer (0.02M sodium q.s. to100 citrate, pH = 5)

Example 6 Antibacterial and Anti-Inflammatory Emulsion

A modification of the procedure of Example 1 is used to produce thisemulsion having the composition shown in the table immediately below.

Polysorbate 60 (Tween 60) is added to water in a first sterilizedstainless steel jacketed vessel, equipped with a stirring mechanism, ata temperature of 50° C. to 60° C. in amounts corresponding theproportions shown in the table below. The resulting aqueous solution isheated to 61° C. to 75° C. At a temperature of 66° C., benzyl alcohol (apreservative) is added to the aqueous solution while mixing three to tenminutes. At a temperature of 75° C., appropriate amounts of the compoundhaving Formula IV and loteprednole etabonate are added to Mygliol oil ina second sterilized vessel, also equipped with a stirring mechanism,over a period of three to five minutes while stirring continues.Sorbitan monostearate and cetyl stearyl alcohol are added to the oilmixture. The resulting oil mixture is heated to a temperature in therange from 62° C. to 75° C. The oil mixture is then added with vigorousmixing to the aqueous solution in the first vessel at a temperature of66° C. over a period of three to five minutes. Sodium sulfate andsulfuric acid and/or sodium hydroxide are added to the mixture to adjustpH to 5.5. The resulting composition is cooled to 35° C. to 45° C. andhomogenized by mixing with a high shear emulsifier or running through ahomogenizer. The composition is further cooled to 25° C. to 30° C. Thefinal composition is packaged in appropriate containers.

Ingredient Amount (% by weight) Compound having Formula IV 0.5Loteprednol etabonate 0.2 Polysorbate 60 1 Sorbitan monostearate 1.5 (anemulsifier) Cetyl stearyl alcohol 1.5 (an emulsion stabilizer) Benzylalcohol 0.5 Miglyol oil 14.5 Na₂SO₄ 1.2 Sulfuric acid and/or NaOH q.s.for pH adjustment to 5.5 Purified water q.s. to 100

Typically, the oil used in an emulsion is a non-irritating emollientoil. Illustrative but non-limiting examples thereof include a mineraloil, vegetable oil, and a reformed vegetable oil of known composition.More specific but non-limiting examples of the oil can be selected fromthe group consisting of peanut oil, sesame seed oil, cottonseed oil, anda medium chain (C₆ to C₁₂) triglycerides (e.g., Miglyol Neutral Oils810, 812, 818, 829, 840, etc., available from Huls America Inc.).Typical emulsifiers employed can be selected from the group consistingof sorbitan monostearate and Tween 60 (also known as Polysorbate 60).Preferably, the emulsifiers are nonionic. The emulsifiers can beemployed in an amount of 1.5 to 6.5% by weight of the composition, andpreferably, 3 to 5% by weight of the composition. The hydrophobic phaseof the emulsion can be in an amount of 15 to 25% by weight of thecomposition, and preferably, 18 to 22% by weight of the composition.

Example 7 Antibacterial, Antifungal, and Anti-Inflammatory Emulsion

A procedure similar to that of Example 6 is used to produce thisemulsion having the following composition.

Ingredient Amount (% by weight) Compound 13 of Table 1 0.5 Butoconazole0.2 Triamcinolone, micronized USP 0.2 Polysorbate 60 1 Sorbitanmonostearate 1.5 Cetyl s earyl alcohol 1.5 Benzyl alcohol 0.5 Miglyoloil 14.5 Na₂SO₄ 1.2 Sulfuric acid and/or NaOH q.s. for pH adjustment to5.5 Purified water q.s. to 100

Example 8 Antibacterial Ointment

A procedure similar to that of Example 1 is used to produce thissolution having the following composition.

Ingredient Amount (% by weight) Compound having Formula VI 0.3 Apramycin0.2 White petrolatum USP 50 Propylene glycol 5 Glycerin 5 Tween ® 20 2Vitamin E 1 BAK 0.1 Mineral oil q.s. to 100

Example 9 Antibacterial and Anti-Inflammatory Ointment

A procedure similar to that of Example 1 is used to produce thissolution having the following composition.

Ingredient Amount (% by weight) Compound having Formula IV 0.3Gatifloxacin 0.1 Dexamethasone 0.15 White petrolatum USP 50 Propyleneglycol 5 Glycerin 5 Tween ® 20 2 Vitamin E 1 Vitamin D 0.5 BAK 0.1Mineral oil q.s. to 100

Example 10 Antibacterial and Antiviral Solution

A procedure similar to that of Example 1 is used to produce thissolution.

Ingredient Amount (% by weight) Compound having Formula IV 0.35 Mannitol4.5 Adenine arabinoside 0.3 Benzakonium chloride (“BAK”) 0.005Polysorbate 80 0.1 EDTA 0.05 Sodium acetate 0.03 Acetic acid 0.04Purified water q.s. to 100

Example 11 Antibacterial and Antifungal Solution

A procedure similar to that of Example 1 is used to produce thissolution.

Ingredient Amount (% by weight) Compound having Formula IV 0.2 Compoundhaving Formula VI 0.2 Amphotericin B 0.3 Mannitol 4.5 Benzakoniumchloride (“BAK”) 0.005 Polysorbate 80 0.1 EDTA 0.05 Sodium acetate 0.03Acetic acid 0.04 Purified water q.s. to 100

Example 12 Antibacterial Emulsion

The procedure of Example 6 is used to produce this emulsion having thecomposition shown in the table immediately below.

Ingredient Amount (% by weight) Compound having Formula IV 0.5Moxifloxacin 0.2 Polysorbate 60 1 Sorbitan monostearate 1.5 (anemulsifier) Cetyl stearyl alcohol (an 1.5 emulsion stabilizer) Benzylalcohol 0.5 Miglyol oil 14.5 Na₂SO₄ 1.2 Sulfuric acid and/or NaOH q.s.for pH adjustment to 5.5 Purified water q.s. to 100

Example 13 Antibacterial Composition Comprising Compound Having FormulaIV and Ciprofloxacin

Compositions having various combinations of concentrations of compoundhaving Formula IV and cirprofloxacin were tested systematically againstS. aureus, P. aeruginosa, and E. coli. The MICs (in μg/ml) of each drugalone and in combination are shown in Table 7.

TABLE 7 MICs of Compound Having Formula IV and Ciprofloxacin Alone andin Combination Compound Having Compound Formula Having Ciprofloxacin IVCiprofloxacin Formula IV in in Organism Alone Alone CombinationCombination S. aureus 0.03 0.5 0.015 0.25 (ATCC 0.0005-0.001  0.5 29213)P. 4 0.5 1 0.25 aeruginosa 1-2 0.012 (ATCC 2 0.06 27853) E. coli 0.120.015-0.030 ≦0.03 0.015 (ATCC 0.015-0.06  0.008 25922) 0.03-0.06 0.0040.03-0.06 0.002 0.015-0.03  0.008 0.06 0.004

Data of Table 7 show that although ciprofloxacin alone is effectiveagainst S. aureus, combinations of the compound having Formula IV andciprofloxacin can be more effective than either drug alone against P.aeruginosa and E. coli as MIC of at least one drug in the combination isless than one-half that of the same drug used alone.

The present invention also provides a method for treating, reducing,ameliorating, or preventing infection of the eye, ear, or upperrespiratory tract. In one aspect, such an infection is caused by mixedtypes of microorganisms including at least a bacterium. In anotheraspect, said at least a bacterium is one that is resistant to at least acommonly used antibiotic. In still another aspect, the method comprisesadministering one or more drops of a composition of the presentinvention to the ear canal, nasal cavity, or back of the throat of asubject who has indication of infection or whose risk of infection isindicated. A composition of the present invention can also be formulatedinto a spray, which can be administered into the otic or nasal cavity ofsuch a subject.

While specific embodiments of the present invention have been describedin the foregoing, it will be appreciated by those skilled in the artthat many equivalents, modifications, substitutions, and variations maybe made thereto without departing from the spirit and scope of theinvention as defined in the appended claims.

1. A synergistic composition for treating, reducing, or ameliorating abacterial infection in a subject comprising: (a) a fluoroquinolonehaving Formula IV or salts thereof; and (b) ciprofloxacin; whereinFormula IV is

and wherein each of the compound having Formula IV and ciprofloxacin ispresent in the composition at a concentration in the range from 0.0001%to 10% by weight of the composition.
 2. The composition of claim 1,wherein the fluoroquinolone is present in an amount from 0.01 to 5% byweight.
 3. The composition of claim 1, wherein the composition furthercomprises an additional anti-infective agent selected from the groupconsisting of antiviral agents, antifungal agents, antiprotozoal agents,antibacterial agents other than the fluoroquinolone having Formula IVand ciprofloxacin, and mixtures thereof.
 4. The composition of claim 3,further comprising an anti-inflammatory agent.
 5. The composition ofclaim 4, wherein said anti-inflammatory agent is selected from the groupconsisting of glucocorticosteroids, non-steroidal anti-inflammatorydrugs, inhibitors of cytokine production, and mixtures thereof.
 6. Thecomposition of claim 5, further comprising a material selected from thegroup consisting of buffers, surfactants, viscosity modifiers, tonicityadjusting agents, preservatives, antioxidants, additional medicaments,and combinations thereof.
 7. The composition of claim 3, wherein thecomposition is in a form of a solution, cream, emulsion, suspension,ointment, or gel.